Abstract
Salvia divinorum is a natural occurring hallucinogen that is traditionally used by the Mazatec Indians of central Mexico. The diterpene salvinorin A was identified as an active component of S. divinorum over 20 years ago, but only recently has biochemical screening indicated that a molecular target of salvinorin A in vitro is the κ-opioid receptor. We have examined whether salvinorin A, the C2-substituted derivative salvinorinyl-2-propionate, and salvinorin B can act as κ-opioid receptor agonists in vivo. We found that following intracerebroventricular injection over a dose range of 1 to 30 μg of both salvinorin A and salvinorinyl-2-propionate produces antinociception in wild-type mice but not in a novel strain of κ-opioid receptor knockout mice. Moreover, both salvinorin A and salvinorinyl-2-propionate reduce rectal body temperature, similar to conventional κ-opioid receptor agonists, in a genotype-dependent manner. In addition, we determined that salvinorin A has high affinity for κ1- but not κ2-opioid receptors, demonstrating selectivity for this receptor subclass. Finally, treatment over the same dose range with salvinorin B, which is inactive in vitro, produced neither antinociceptive nor hypothermic effects in wild-type mice. These data demonstrate that salvinorin A is the active component of S. divinorum, selective for κ1-opioid receptors, and that salvinorin A and specific structurally related analogs produce behavioral effects that require the κ-opioid receptor.
Footnotes
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This work was supported by National Institutes of Health (NIH) Grants DA-009040 and DA-015237 (to J.E.P.), the Intramural Research Program of the NIH, and National Institute of Drug Abuse (NIDA) (to R.B.R.), NIH, Grants DA-017204 (to B.L.R.) and MH/AG 19957 and F32 DA-14755 (to M.A.A.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.101998.
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ABBREVIATIONS: KORs, κ-opioid receptors; i.c.v., intracerebroventricularly; KO, knockout; kb, kilobase; neo, neomycin; U69,593, (+)-(5a,7a,8b)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspirodec-8-yl]-benzeneacetamide; HRMS, high-resolution mass spectrometry; BIT, 2-(p-ethoxybenzyl)-1-DEAE-5-isothiocyanatobenzimidazole-HCl; FIT, N-phenyl-N-[1-(2-(p-isothiocyanato)phenylethyl)-4-piperidinyl]propanamide-HCl; DMSO, dimethyl sulfoxide; %MPE, percentage maximal possible effect; U50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidiny)-cyclohexyl]-benzeneacetamide; ANOVA, analysis of variance; PLSD, protected least significant difference; ES, embryonic stem.
- Received January 27, 2006.
- Accepted May 2, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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